High density epidural stimulation for facilitation of locomotion, posture, voluntary movement, and recovery of autonomic, sexual, vasomotor, and cognitive function after neurological injury

ABSTRACT

Methods of enabling locomotor control, postural control, voluntary control of body movements (e.g., in non-weight bearing conditions), and/or autonomic functions in a human subject having spinal cord injury, brain injury, or neurological neuromotor disease. In certain embodiments, the methods involve stimulating the spinal cord of the subject using an epidurally placed electrode array, subjecting the subject to physical training thereby generating proprioceptive and/or supraspinal signals, and optionally administering pharmacological agents to the subject. The combination of stimulation, physical training, and optional pharmacological agents modulate in real time electrophysiological properties of spinal circuits in the subject so they are activated by supraspinal information and/or proprioceptive information derived from the region of the subject where locomotor activity is to be facilitated.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant No.W81XWH-09-2-0024, awarded by the United States Army, Medical Researchand Materiel Command; and Grant No. EB007615, awarded by the NationalInstitutes of Health. The Government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field neurological rehabilitationincluding traumatic spinal cord injury, non-traumatic spinal cordinjury, stroke, movement disorders, brain injury, and other diseases orinjuries that result in paralysis and/or nervous system disorder.Devices, pharmacological agents, and methods are provided to facilitaterecovery of posture, locomotion, and voluntary movements of the arms,trunk, and legs, and recovery of autonomic, sexual, vasomotor, andcognitive function, in a human subject having spinal cord injury, braininjury, or any other neurological disorder.

2. Description of the Related Art

Serious spinal cord injuries (SCI) affect approximately 250,000 peoplein the United States, and roughly 11,000 new injuries occur each year.Of these injuries, approximately 50% are complete spinal cord injuriesin which there is essentially total loss of sensory motor function belowthe level of the spinal lesion.

For chronic SCI humans, impressive levels of standing and steppingrecovery has been demonstrated in certain incomplete SCI subjects withtask specific physical rehabilitation training. A recent clinical trialdemonstrated that 92% of the subjects regained stepping ability toalmost a functional speed of walking three months after a severe yetincomplete injury (Dobkin et al., Neurology, 66(4): 484-93 (2006)) andin chronic subjects months to years after injury (Harkema et. al.,Archives of Physical Medicine and Rehabilitation: 2011 epub).Furthermore, improved coordination of motor pool activation can beachieved with training in patients with incomplete SCI (Field-Fote etal., Phys. Ther., 82 (7): 707-715 (2002)). On the other hand, there isno generally accepted evidence that an individual with a clinicallycomplete SCI can be trained to the point where they could stand orlocomote even with the aid of a “walker” (Wernig, Arch Phys MedRehabil., 86(12): 2385-238 (2005)) and no one has shown the ability toregain voluntary movements and/or to recover autonomic, sexual,vasomotor, and/or improved cognitive function after a motor completespinal cord injury.

To date, the consistently most successful intervention for regainingweight-bearing stepping in humans is weight-bearing step training, butthat has been the case primarily in subjects with incomplete injuries.

The most effective future strategies for improving motor and autonomicfunctions that improve the quality of life post-SCI will likely involvethe combination of many different technologies and strategies, asneurological deficits such as spinal cord injuries are complex, andthere is a wide variability in the deficit profile among patients. Inthe long run, neuro-regenerative strategies hold significant promise forfunctional sensory-motor recovery from traumatic and progressiveneurological deficits. Progress is already being made particularly inthe case of acute treatment of incomplete spinal injuries. However, evenwhen these strategies are perfected, other remedies will be needed. Itis naive to think that neuro-regenerative approaches will recover fullyfunctional postural and locomotor function as well as voluntary controlof lower limb, and voluntary upper limb movement following a motorcomplete spinal injury.

SUMMARY OF THE INVENTION

Embodiments of the invention are for use with a human patient (orsubject) who has a spinal cord with at least one selected spinal circuitand a neurologically derived paralysis in a portion of the patient'sbody. By way of non-limiting examples, when activated, the selectedspinal circuit may (a) enable voluntary movement of muscles involved inat least one of standing, stepping, reaching, grasping, voluntarilychanging positions of one or both legs, voiding the patient's bladder,voiding the patient's bowel, postural activity, and locomotor activity;(b) enable or improve autonomic control of at least one ofcardiovascular function, body temperature, and metabolic processes;and/or (c) help facilitate recovery of at least one of an autonomicfunction, sexual function, vasomotor function, and cognitive function.

The paralysis may be a motor complete paralysis or a motor incompleteparalysis. The paralysis may have been caused by a spinal cord injuryclassified as motor complete or motor incomplete. The paralysis may havebeen caused by an ischemic or traumatic brain injury. The paralysis mayhave been caused by an ischemic brain injury that resulted from a strokeor acute trauma. By way of another example, the paralysis may have beencaused by a neurodegenerative brain injury. The neurodegenerative braininjury may be associated with at least one of Parkinson's disease,Huntington's disease, Alzheimer's, ischemia, stroke, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), and cerebral palsy.

One exemplary embodiment is a method that includes positioning the humanpatient in a training device. The training device is configured toassist with physical training (e.g., at least one of standing, stepping,reaching, moving one or both legs, moving one or both feet, grasping,and stabilizing sitting posture) that is configured to induceneurological signals (e.g., at least one of postural proprioceptivesignals, locomotor proprioceptive signals, and supraspinal signals) inthe portion of the patient's body having the paralysis. The trainingdevice may include a robot training device configured to moveautomatically at least a portion of the portion of the patient's bodyhaving the paralysis. By way of non-limiting example, the trainingdevice may include a treadmill and a weight-bearing device configured tosupport at least a portion of the patient's body weight when the patientis positioned to use the treadmill. By way of another non-limitingexample, the training device may include a device configured to bear atleast a portion of the patient's body weight when the patienttransitions between sitting and standing.

The selected spinal circuit has a first stimulation thresholdrepresenting a minimum amount of stimulation required to activate theselected spinal circuit, and a second stimulation threshold representingan amount of stimulation above which the selected spinal circuit isfully activated and adding the induced neurological signals has noadditional effect on the at least one selected spinal circuit. Theinduced neurological signals are below the first stimulation thresholdand insufficient to activate the at least one selected spinal circuit.

The method also includes applying electrical stimulation to a portion ofa spinal cord of the patient. The electrical stimulation may be appliedby an electrode array that is implanted epidurally in the spinal cord ofthe patient. Such an electrode array may be positioned at at least oneof a lumbosacral region, a cervical region, and a thoracic region of thespinal cord. The electrical stimulation is below the second stimulationthreshold such that the at least one selected spinal circuit is at leastpartially activatable by the addition of at least one of (a) a secondportion of the induced neurological signals, and (b) supraspinalsignals. While not a requirement, the first portion of the inducedneurological signals may be the same as the second portion of theinduced neurological signals. While also not a requirement, theelectrical stimulation may not directly activate muscle cells in theportion of the patient's body having the paralysis. The electricalstimulation may include at least one of tonic stimulation andintermittent stimulation. The electrical stimulation may includesimultaneous or sequential stimulation of different regions of thespinal cord.

If the paralysis was caused by a spinal cord injury at a first locationalong the spinal cord, the electrical stimulation may be applied by anelectrode array that is implanted epidurally on the spinal cord of thepatient at a second location below the first location along the spinalcord relative to the patient's brain.

Optionally, the method may include administering one or moreneuropharmaceutical agents to the patient. The neuropharmaceuticalagents may include at least one of a serotonergic drug, a dopaminergicdrug, a noradrenergic drug, a GABAergic drug, and glycinergic drugs. Byway of non-limiting examples, the neuropharmaceutical agents may includeat least one of 8-OHDPAT, Way 100.635, Quipazine, Ketanserin, SR 57227A,Ondanesetron, SB 269970, Methoxamine, Prazosin, Clonidine, Yohimbine,SKF-81297, SCH-23390, Quinpirole, and Eticlopride.

The electrical stimulation is defined by a set of parameter values, andactivation of the selected spinal circuit may generate a quantifiableresult. Optionally, the method may be repeated using electricalstimulation having different sets of parameter values to obtainquantifiable results generated by each repetition of the method. Then, amachine learning method may be executed by at least one computingdevice. The machine learning method builds a model of a relationshipbetween the electrical stimulation applied to the spinal cord and thequantifiable results generated by activation of the at least one spinalcircuit. A new set of parameters may be selected based on the model. Byway of a non-limiting example, the machine learning method may implementa Gaussian Process Optimization.

Another exemplary embodiment is a method of enabling one or morefunctions selected from a group consisting of postural and/or locomotoractivity, voluntary movement of leg position when not bearing weight,voluntary voiding of the bladder and/or bowel, return of sexualfunction, autonomic control of cardiovascular function, body temperaturecontrol, and normalized metabolic processes, in a human subject having aneurologically derived paralysis. The method includes stimulating thespinal cord of the subject using an electrode array while subjecting thesubject to physical training that exposes the subject to relevantpostural proprioceptive signals, locomotor proprioceptive signals, andsupraspinal signals. At least one of the stimulation and physicaltraining modulates in real time the electrophysiological properties ofspinal circuits in the subject so the spinal circuits are activated byat least one of supraspinal information and proprioceptive informationderived from the region of the subject where the selected one or morefunctions are facilitated.

The region where the selected one or more functions are facilitated mayinclude one or more regions of the spinal cord that control (a) lowerlimbs; (b) upper limbs; (c) the subject's bladder; and/or (d) thesubject's bowel. The physical training may include standing, stepping,sitting down, laying down, reaching, grasping, stabilizing sittingposture, and/or stabilizing standing posture.

The electrode array may include one or more electrodes stimulated in amonopolar configuration and/or one or more electrodes stimulated in abipolar configuration. The electrode array includes a plurality ofelectrodes that may have an interelectrode spacing between adjacentelectrodes of about 500 μm to about 1.5 mm. The electrode array may bean epidurally implanted electrode array. Such an epidurally implantedelectrode array may be placed over at least one of a lumbosacral portionof the spinal cord, a thoracic portion of the spinal cord, and acervical portion of the spinal cord.

The stimulation may include tonic stimulation and/or intermittentstimulation. The stimulation may include simultaneous or sequentialstimulation of different spinal cord regions. Optionally, thestimulation pattern may be under control of the subject.

The physical training may include inducing a load bearing positionalchange in the region of the subject where locomotor activity is to befacilitated. The load bearing positional change in the subject mayinclude standing, stepping, reaching, and/or grasping. The physicaltraining may include robotically guided training.

The method may also include administering one or moreneuropharmaceuticals. The neuropharmaceuticals may include at least oneof a serotonergic drug, a dopaminergic drug, a noradrenergic drug, aGABAergic drug, and a glycinergic drug.

Another exemplary embodiment is a method that includes implanting anelectrode array on the patient's spinal cord, positioning the patient ina training device configured to assist with physical training that isconfigured to induce neurological signals in the portion of thepatient's body having the paralysis, and applying electrical stimulationto a portion of a spinal cord of the patient. The induced neurologicalsignals is below the first stimulation threshold and insufficient toactivate the at least one selected spinal circuit. The electricalstimulation is below the second stimulation threshold such that the atleast one selected spinal circuit is at least partially activatable bythe addition of at least one of (a) a second portion of the inducedneurological signals, and (b) supraspinal signals. Optionally, theelectrode array may be implanted on the dura of the patient's spinalcord.

Another exemplary embodiment is a system that includes a training deviceconfigured to assist with physically training of the patient, animplantable electrode array configured to be implanted on the dura ofthe patient's spinal cord, a stimulation generator connected to theimplantable electrode array. When undertaken, the physical traininginduces neurological signals in the portion of the patient's body havingthe paralysis. The stimulation generator is configured to applyelectrical stimulation to the implantable electrode array.Electrophysiological properties of at least one spinal circuit in thepatient's spinal cord is modulated by the electrical stimulation and atleast one of (1) a first portion of the induced neurological signals and(2) supraspinal signals such that the at least one spinal circuit is atleast partially activatable by at least one of (a) the supraspinalsignals and (b) a second portion of the induced neurological signals.The induced neurological signals and supraspinal signals are below thefirst stimulation threshold and insufficient to activate the at leastone selected spinal circuit, and the electrical stimulation applied tothe implantable electrode array is below the second stimulationthreshold.

Another exemplary embodiment is a system that includes means forphysically training the patient to induce neurological signals in theportion of the patient's body having the paralysis, and means forapplying electrical stimulation to a portion of a spinal cord of thepatient. Electrophysiological properties of at least one spinal circuitin the patient's spinal cord being modulated by the electricalstimulation and at least one of a first portion of the inducedneurological signals and supraspinal signals such that the at least onespinal circuit is at least partially activatable by at least one of (a)the supraspinal signals and (b) a second portion of the inducedneurological signals.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 summarizes recent experiments in rats that were carried out toassess the effectiveness of epidural stimulation coupled with combineddrug therapy in the treatment of complete spinal cord injuries. Thecombination of quipazine and 8-0HDPAT with simultaneous epiduralstimulation at spinal sites L2 and S1 results in robust coordinatedstepping as early as one week after a complete spinal cord transection.Locomotor behavior observed from a typical rat before the injury and oneweek after a complete mid-thoracic spinal cord transection. The amountof body weight support provided to the rat is shown in red. One weekpost-injury, no spontaneous stepping activity is observed.Administration of quipazine (a 5-HT₂ receptor agonist) and 8-0HDPAT (a5-HT_(1/7) receptor agonist) results in erratic movements. Epiduralstimulation simultaneously at L2 plus S1 in combination with eitherquipazine or 8-0HDPAT enables plantar stepping. The combination ofepidural stimulation at L2 plus S1 with the administration of quipazineplus 8-0HDPAT clearly has a synergistic effect, resulting incoordinated, plantar stepping with features resembling those observedpre-lesion. Sol, soleus; TA, tibialis anterior; MTP,metatarsal-phalangeal.

FIG. 2 illustrates step training with epidural stimulation at both L2and S1 spinal sites in combination with use of quipazine and 8-0HDAPT(5-HT agonists) prevents degradation of neuronal function and promotesimprovement of the stepping ability of spinal rats transected as adults.From top to bottom: Representative stick diagrams of left and righthindlimb movements during gait swing phase, recorded 8 weekspost-injury. The successive trajectories of the left and right limbendpoint (MTP) during a 10 s stepping sequence are shown. Blue, red, andblack trajectories represent stance, drag, and swing phases. The gaitdiagrams reconstructed from the displacement of the left and righthindlimbs during stepping are displayed conjointly with the EMG activityof left and right soleus (“Sol”) and tibialis anterior (“TA”) muscles.Compared to a rat with no rehabilitation, the rat that received steptraining every other day for 7 weeks shows consistent hindlimbmovements, coordination between the left and right sides, and increasedrecruitment of both extensor and flexor leg muscles.

FIG. 3 shows a photograph of an illustrative 1st generation high densityepidural stimulating array comprising 10 electrodes.

FIG. 4 shows a schematic diagram of an illustrative laminectomyprocedure for placing an epidural stimulating array over the lumbosacralspinal cord.

FIG. 5 panels A-D illustrates results for site-specific selective muscleactivation. The extensor digitorum longus (EDL, panel A), vastuslateralis (VL, panel B), and tibialis anterior (TA, panel C) muscleswere selectively activated using low-current stimulation at specificspinal sites. Preferential activation of the medial gastrocnemius (MG,panel D) muscle also was obtained, but occurred with co-activation ofthe VL. Data represent normalized peak-to-peak amplitudes of 10 averagedresponses.

FIG. 6 shows that interelectrode distance modulates muscle recruitment.Using a smaller spacing (1500 μm, filled bars) bipolar configuration,graded muscle activation was achieved. With larger spacing (4500 μm,unfilled bars), approaching a monopolar configuration, a muscle quicklyattained maximal activation at low currents. Thus, the specific goal andsensitivity requirements of a particular motor task may dictate optimalinterelectrode spacing and whether a monopolar or bipolar configurationis chosen.

FIG. 7 shows a photograph of an illustrative 27 electrode rat epiduralstimulation array (in a 9×3 configuration), including head-connector.

FIG. 8 shows a photograph of an illustrative 256 electrode array.

FIG. 9 illustrates a schematic of a step training robot. Illustrativecomponents include: A) Optical encoder; B) Motor; C) Weight support; D)Manipulators; and E) Motorized treadmill.

FIGS. 10A and 10B show radiographic and clinical characteristics of anindividual with motor complete, but sensory incomplete SCI. FIG. 10A: T2weighted sagittal Magnetic Resonance Image of cervical spine atsubject's injury site (C7-T1). Hyperintensity and myelomalacia noted atsite of injury. FIG. 10B: AIS evaluation of the subject.

FIGS. 11A-11D illustrate localization of electrode array relative tomotoneuron pools as identified with motor evoked potentials duringsurgical implantation. The voltage thresholds for evoked potentials ofproximal muscles are lower when stimulating the more rostral electrodes.The voltage thresholds for motor evoked potentials of the distal musclesare lower when stimulating the caudal electrodes. FIG. 11A:Post-operative fluoroscopy of the thoracolumbar spine showing thelocation of the implanted electrode array and neurostimulator. FIG. 11B:Depiction of 16-electrode array configuration relative to spinal dorsalroots and corresponding motoneuron pools identified using EMG recordedfrom leg muscles. FIGS. 11C and 11D: Motor evoked potentials elicitedusing epidural stimulation at 2 Hz, 210 μs from 0.0 to 7 V with rostralelectrodes, (5−: 6+) and caudal electrodes (10−: 9+) respectively.Muscles: IL: iliopsoas, AD: adductor magnus, VL: vastus lateralis, MH:medial hamstrings, TA: tibialis anterior, GL: gluteus maximus, SL:soleus, MG: medial gastrocnemius.

FIG. 12 illustrates lower extremity EMG activity during standing withBWST (panel A), and stepping with body weight support (“BWST”) (panelB). Three different time points over a two-year period and 170 trainingsessions showed no change in the EMG pattern during standing orstepping.

FIG. 13 shows EMG activity with epidural stimulation during independentstanding. These data demonstrate that the output of the spinal circuitrycan be sufficiently modulated by the proprioceptive input to sustainindependent stepping. EMG activity increases in amplitude and becomesmore constant bilaterally in most muscles with independent standingoccurring at 8 V. Reducing BWS changed the EMG amplitudes andoscillatory patterns differently among muscles. EMG activity duringstanding with BWS and with epidural stimulation (15 Hz) of caudallumbosacral segments (4/10/15−: 3/9+) (panel A) from 1-8V and 65% BWSand (panel B) at 8V while reducing the BWS from 45% to 5%. Muscle:rectus femoris (RF), medial hamstrings (MH), tibialis anterior (TA), andmedial gastrocnemius (MG). Left (L) and right (R).

FIG. 14 illustrates lower extremity EMG activity during sitting andstanding with and without epidural stimulation. There was little or noEMG activity without stimulation, but with epidural stimulation therewas significant EMG activity that was modulated during the transitionfrom sitting to standing. Panel A: EMG activity during sitting (green)and standing (yellow) with no epidural stimulation. Panel B: EMGactivity during sitting (green) and standing (yellow) with 4V to 7.5 V,15 Hz stimulation of the rostral lumbar segments (0/5/11−: 1/6/12+).Panel C: EMG activity during sitting (green) and standing (yellow) withepidural stimulation (15 Hz) of the caudal lumbosacral segments(4/10/15−: 3/9/14+). Panel D: Averaged mean amplitude (mV) of right sidemotor evoked responses during sitting and standing elicited fromepidural stimulation (b) or rostal stimulation is represented by “▴,”(c) or caudal stimulation is represented by “♦,” and no stimulation isrepresented by opened circles (∘). No stimulation values are only shownfor sitting and standing. Panel E: Kinematic representation oftransition from sitting to standing with caudal stimulation. Muscles:iliopsoas (IL), vastus lateralis (VL), medial hamstrings (MH), tibialisanterior (TA), soleus (Sol), and medial gastrocnemius (MO). Left sidemuscles (L), right side muscles (R).

FIG. 15 illustrates EMG activity with epidural stimulation duringindependent standing. Panel A: EMG activity with epidural stimulation (8V, 15 Hz) of the caudal lumbosacral segments (4/10/15−: 3/9/14+) duringweight shifting. Body movements are depicted in the top panel asdisplacement of the center of gravity (CGX) lateral shifting (CGY) tothe right (R)) and left (L) sides in the bottom panels. Panel B: EMGactivity with epidural stimulation during independent standing.Interpulse interval depicting stimulation frequency is shown on thelower right of the top and bottom graphs. Red line indicates initiationof independent standing as subject counted backwards from 3, blue lineindicates when independent standing was obtained. Muscle: iliopsoas(IL), rectus femoris (RF), medial hamstrings (MH), tibialis anterior(TA), Soleus (SOL) and medial gastrocnemius (MG). Left (L) and right(R).

FIG. 16 shows lower extremity EMG activity during standing and steppingwith body weight support and manual facilitation with and withoutepidural stimulation of caudal lumbosacral segments. The EMG patternswere modified by the intensity of stimulation and by different patternsof sensory input. EMG activity during stepping (50% BWS, 1.07 m/s)(panel A) without stimulation and (panel B) (45% BWS, 0.8 m/s) withepidural stimulation (5.5 V, 30 Hz) of caudal lumbosacral segments(4/10/15−: 3/9+). EMG activity during (panel C) standing (25% BWS) and(panels B, D) stepping (50% BWS, 1.07 m/s) with epidural stimulation(7.0 V, 30 Hz) of caudal lumbosacral segments (4/10/15−: 3/9+) (panelC). For stepping (panels B, C, and D) data were selected from 5consecutive cycles. Muscles: vastus lateralis (VL), medial hamstrings(MH), tibialis anterior (TA), and medial gastrocnemius (MG). Left (L)and right (R) side muscles. Load is load cell reading in Newtons (N).Left (LHip) and Right (RHip) are sagittal joint angles for the hipjoint. Left (LFS) and right (RFS) footswitches reflect stance phase.

FIGS. 17A-17E show lower extremity EMG activity during voluntary controlin a supine position with and without stimulation. The black barindicates the command to generate flexion and move the left leg up (FIG.17A), left ankle dorsiflexion (FIG. 17B), and left toe extension (FIG.17C), and the white bar indicates the command to relax the leg. Left andright sides are shown to emphasize the isolated control of the left sidefollowing the command. The right and left intercostals (IC) areactivated during the voluntary attempt of the leg, as the subjectinhales as he attempts to perform the movement. Muscles: soleus (SOL),extensor digitorum longus (EDL), extensor hallucis longus (EHL),tibialis anterior (TA), peroneus longus (PL), vastus lateralis (VL),medial hamstrings (MH), adductor magnus (AD), gluteus maximus (GL),iliopsoas (IL), erector spinae (ES), rectus abdominus (AB), intercostals(IC). Sagittal joint angles for the toe (1st metatarsal relative tofoot), ankle, knee, and hip joints. FIG. 17D: Stick figures weregenerated from the kinematics during the up and down commands for bothtrials with and without epidural stimulation. FIG. 17E: Relationshipbetween onset (solid)/offset (open) of EMG burst for TA muscle andcommand up/down. Three trials were performed for the toe and legvoluntary movements and two trials for the ankle. All commands weregiven to move the left leg. The dotted line represents the line ofidentity (x=y).

FIG. 18A shows a 3D view of epidural spinal electrode (with 2 of 27electrodes activated) placed in the epidural space of a simulated spinalcord.

FIG. 18B shows isopotential contours of electrical field (in slicethrough center of bipolarly activated electrodes). Model compartmentsinclude gray matter, white matter, CSF, epidural fat, and surroundingbody tissue.

FIG. 19 (top) shows instantaneous regret (a measure of machine learningerror) vs. learning iteration (labeled as “query number”) for GaussianProcess Optimization of array stimulation parameters in the simulatedspinal cord of FIGS. 18A and 18B. The “bursts” of poor performancecorresponds to excursions of the learning algorithm to regions ofparameter space that are previously unexplored, but which are found tohave poor performance. FIG. 19 (bottom) shows the average cumulativeregret vs. learning iteration. The average cumulative regret is asmoothed version of the regret performance function which better showsthe algorithm's overall progress in selecting optimal stimulationparameters.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The term “motor complete” when used with respect to a spinal cord injuryindicates that there is no motor function below the lesion, (e.g., nomovement can be voluntarily induced in muscles innervated by spinalsegments below the spinal lesion (e.g., as described below in Example1).

The term “bipolar stimulation” refers to stimulation between two closelyspaced electrodes.

The term “monopolar stimulation” refers to stimulation between a localelectrode and a common distant return electrode.

The term “autonomic function” refers to functions controlled by theperipheral nervous system that are controlled largely below the level ofconsciousness, and typically involve visceral functions. Illustrativeautonomic functions include, but are not limited to control of bowel,bladder, and body temperature.

The term “sexual function” refers to the ability to sustain a penileerection, have an orgasm (male or female), generate viable sperm, and/orundergo an observable physiological change associated with sexualarousal.

The term “cognitive function” refers to awareness of one's surroundingenvironment and the ability to function effectively, behaviorally, andmentally in a given environment.

In various embodiments, methods, devices, and optional pharmacologicalagents are provided to facilitate movement in a mammalian subject (e.g.,a human) having spinal cord injury, brain injury, or other neurologicaldisease or injury. In certain embodiments, the methods involvestimulating the spinal cord of the subject using an electrode arraywhere the stimulation modulates the electrophysiological properties ofselected spinal circuits in the subject so they can be activated byproprioceptive derived information and/or input from supraspinal. Invarious embodiments, the stimulation is typically accompanied byphysical training (e.g., movement) of the region where the sensory-motorcircuits of the spinal cord are located.

In particular illustrative embodiments, the devices, optionalpharmacological agents, and methods described herein stimulate thespinal cord with, e.g., electrode arrays, that modulate theproprioceptive and supraspinal information which controls the lowerlimbs during standing and/or stepping and/or the upper limbs duringreaching and/or grasping conditions. It is the sensory information thatguides the activation of the muscles in a coordinated manner and in amanner that accommodates the external conditions, e.g., the amount ofloading, speed, and direction of stepping or whether the load is equallydispersed on the two lower limbs, indicating a standing event,alternating loading indicating stepping, or sensing postural adjustmentssignifying the intent to reach and grasp.

Unlike approaches that involve specific stimulation of motor neurons todirectly induce a movement, the methods described herein enable thespinal circuitry to control the movements. More specifically, thedevices, optional pharmacological agents, and methods described hereinexploit the spinal circuitry and its ability to interpret proprioceptiveinformation and to respond to that proprioceptive information in afunctional way. In various embodiments, this is in contrast to otherapproaches where the actual movement is induced/controlled by directstimulation (e.g., of particular motor neurons).

In one illustrative embodiment, the subject is fitted with one or moreimplantable electrode arrays that afford selective stimulation andcontrol capability to select sites, mode(s), and intensity ofstimulation via electrodes placed epidurally over, for example, thelumbosacral spinal cord and/or cervical spinal cord to facilitatemovement of the arms and/or legs of individuals with a severelydebilitating neuromotor disorder.

The subject receives the implant (a standard procedure when used forpain alleviation), and typically about two weeks post implant, thesubject is tested to identify the most effective subject specificstimulation paradigms for facilitation of movement (e.g., stepping andstanding and/or arm and/or hand movement). Using these stimulationparadigms, the subject practices standing and stepping and/or reachingor grabbing in an interactive rehabilitation program while being subjectto spinal stimulation.

Depending on the site/type of injury and the locomotor activity it isdesired to facilitate, particular spinal stimulation protocols include,but are not limited to specific stimulation sites along the lumbosacraland/or cervical spinal cord; specific combinations of stimulation sitesalong the lumbosacral and/or cervical spinal cord; specific stimulationamplitudes; specific stimulation polarities (e.g., monopolar and bipolarstimulation modalities); specific stimulation frequencies; and/orspecific stimulation pulse widths.

In various embodiments, the system is designed so that the patient canuse and control it in the home environment.

In various embodiments, the approach is not to electrically induce awalking pattern or standing pattern of activation, but toenable/facilitate it so that when the subject manipulates their bodyposition, the spinal cord can receive proprioceptive information fromthe legs (or arms) that can be readily recognized by the spinalcircuitry. Then, the spinal cord knows whether to step or to stand or todo nothing. In other words, this enables the subject to begin steppingor to stand or to reach and grasp when they choose after the stimulationpattern has been initiated.

Moreover, as demonstrated in Example 1 (described below), the methodsand devices described herein are effective in a spinal cord injuredsubject that is clinically classified as motor complete; that is, thereis no motor function below the lesion. In various embodiments, thespecific combination of electrodes activated/stimulated within an arrayand/or the desired stimulation of any one or more electrodes and/or thestimulation amplitude (strength) can be varied in real time, e.g., bythe subject. Closed loop control can be embedded in the process byengaging the spinal circuitry as a source of feedback and feedforwardprocessing of proprioceptive input and by voluntarily imposing finetuning modulation in stimulation parameters based on visual, and/orkinetic, and/or kinematic input from selected body segments.

In various embodiments, the devices, optional pharmacological agents,and methods are designed so that a subject with no voluntary movementcapacity can execute effective standing and/or stepping and/or reachingand/or grasping. In addition, the approach described herein can play animportant role in facilitating recovery of individuals with severealthough not complete injuries.

The approach described herein can provide some basic postural, locomotorand reaching and grasping patterns on their own. However, they are alsolikely to be a building block for future recovery strategies. Based oncertain successes in animals and some preliminary human studies (seebelow), it appears that a strategy combining effective epiduralstimulation of the appropriate spinal circuits with physicalrehabilitation and pharmacological intervention can provide practicaltherapies for complete SCI human patients. There is sufficient evidencefrom our work that such an approach should be enough to enable weightbearing standing, stepping and/or reaching or grasping. Such capabilitycan give complete SCI patients the ability to participate in exercise,which is known to be highly beneficial for their physical and mentalhealth. We also expect our method should enable movement with the aid ofassistive walkers. While far from complete recovery of all movements,even simple standing and short duration walking would increase thesepatients' autonomy and quality of life. The stimulating array technologydescribed herein (e.g., epidural stimulating arrays) paves the way for adirect brain-to-spinal cord interface that could enable more lengthy andfiner control of movements.

While the methods and devices described herein are discussed withreference to complete spinal injury, it will be recognized that they canapply to subjects with partial spinal injury, subjects with braininjuries (e.g., ischemia, traumatic brain injury, stroke, and the like),and/or subjects with neurodegenerative diseases (e.g., Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), cerebral palsy, andthe like).

In various embodiments, the methods combine the use of epiduralstimulating arrays with physical training (e.g., rigorously monitored(robotic) physical training), optionally in combination withpharmacological techniques. The methods enable the spinal cord circuitryto utilize sensory input as well as newly established functionalconnections from the brain to circuits below the spinal lesion as asource of control signals. The approach is thus designed to enable andfacilitate the natural sensory input as well as supraspinal connectionsto the spinal cord in order to control movements, rather than induce thespinal cord to directly induce the movement. That is, we facilitate andenhance the intrinsic neural control mechanisms of the spinal cord thatexist post-SCI, rather than replace or ignore them.

Processing of Sensory Input by the Lumbosacral Spinal Cord: UsingAfferents as a Source of Control

In various embodiments the methods and devices described herein exploitspinal control of locomotor activity. For example, the human spinal cordcan receive sensory input associated with a movement such as stepping,and this sensory information can be used to modulate the motor output toaccommodate the appropriate speed of stepping and level of load that isimposed on lower limbs. Moreover, we have demonstrated that the humanlumbosacral spinal cord has central-pattern-generation-like properties.Thus, oscillations of the lower limbs can be induced simply by vibratingthe vastus lateralis muscle of the lower limb, by epidural stimulation,and by stretching the hip. The methods described herein exploit the factthat the human spinal cord, in complete or incomplete SCI subjects, canreceive and interpret proprioceptive and somatosensory information thatcan be used to control the patterns of neuromuscular activity among themotor pools necessary to generate particular movements, e.g., standing,stepping, reaching, grasping, and the like. The methods described hereinfacilitate and adapt the operation of the existing spinal circuitry thatgenerates, for example, cyclic step-like movements via a combinedapproach of epidural stimulation, physical training, and, optionally,pharmacology.

Facilitating Stepping and Standing in Humans Following a ClinicallyComplete Lesion

Locomotion in mammals is attributed to intrinsic oscillating spinalneural networks capable of central pattern generation interacting withsensory information (Edgerton et al., J. American Paraplegia Soc, 14(4)(1991), 150-157; Forssberg, J. Neurophysiol, 42(4): 936-953 (1979);Grillner and Wallen, Annu. Rev. Neurosci., 8: 233-261 (1985); Grillnerand Zangger, Exp Brain Res, 34(2): 241-261 (1979)). These networks playcritical roles in generating the timing of the complex postural andrhythmic motor patterns executed by motor neurons.

As indicated above, the methods described herein can involve stimulationof one or more regions of the spinal cord in combination with locomotoryactivities. It was our discovery that spinal stimulation in combinationwith locomotor activity results in the modulation of theelectrophysiological properties of spinal circuits in the subject sothey are activated by proprioceptive information derived from the regionof the subject where locomotor activity is to be facilitated. Further,we also determined that spinal stimulation in combination withpharmacological agents and locomotor activity results in the modulationof the electrophysiological properties of spinal circuits in the subjectso they are activated by proprioceptive information derived from theregion of the subject where locomotor activity is to be facilitated.

Locomotor activity of the region of interest can be accomplished by anyof a number of methods known, for example, to physical therapists. Byway of illustration, individuals after severe SCI can generate standingand stepping patterns when provided with body weight support on atreadmill and manual assistance. During both stand and step training ofhuman subjects with SCI, the subjects can be placed on a treadmill in anupright position and suspended in a harness at the maximum load at whichknee buckling and trunk collapse can be avoided. Trainers positioned,for example, behind the subject and at each leg assist as needed inmaintaining proper limb kinematics and kinetics appropriate for eachspecific task. During bilateral standing, both legs can be loadedsimultaneously and extension can be the predominant muscular activationpattern, although co-activation of flexors can also occur. Additionally,or alternatively, during stepping the legs are loaded in an alternatingpattern and extensor and flexor activation patterns within each limbalso alternated as the legs moved from stance through swing. Afferentinput related to loading and stepping rate can influence these patterns,and training has been shown to improve these patterns and function inclinically complete SCI subjects.

Epidural Stimulation of the Lumbosacral Spinal Cord

As indicated above, without being bound by a particular theory, it isbelieved that epidural stimulation, e.g., over the lumbosacral spinalcord in combination with physical training can facilitate recovery ofstepping and standing in human subjects following a complete SCI.

Spinal cord electrical stimulation has been successfully used in humansfor suppression of pain and spasticity (see, e.g., Johnson and Burchiel,Neurosurgery, 55(1): 135-141 (2004); discussion 141-142; Shealy et al.,Anesth Analg, 46(4): 489-491 (1967); Campos et al., Appl. Neurophysiol.50(1-6): 453-454 (1987); Dimitrijevic and Sherwood, Neurology, 30 (7 Pt2): 19-27 (1980); Barolat Arch. Med. Res., 31(3): 258-262 (2000);Barolat, J. Am. Paraplegia Soc., 11(1): 9-13 (1988); Richardson et al.,Neurosurgery, 5(3): 344-348). Recent efforts to optimize electrodedesign and stimulation parameters have led to a number of researchstudies focusing on the benefits of epidural spinal cord stimulation. Wehave demonstrated that the location of the electrode array and itsstimulation parameters are important in defining the motor response. Useof high density electrode arrays, as described herein, facilitatesselection or alteration of particular stimulation sites as well as theapplication of a wide variety of stimulation parameters.

FIG. 1 summarizes experiments in rats that were carried out to assessthe effectiveness of epidural stimulation coupled with combined drugtherapy in acute treatment of complete spinal cord injury. Theseexperiments also show that pharmacological intervention provides somerecovery of stepping function, but that epidural stimulation coupledwith drug therapy recovers significant amounts of stepping ability evenone week after a complete spinal transaction.

FIG. 2 compares two adult rats with complete spinal cord transections atthe end of a 7 week period during which both animals were given bothdrug therapy as well as epidural stimulation (using conventionalrod-electrodes at two spinal sites). The animal which was also givenrobotically guided physical therapy showed significant improvement overthe animal which did not receive physical training. These resultsprovide support for our assertion that a strategy that combines physicaltherapy with epidural stimulation and, optional, pharmacologicalmodulation of the post-SCI spinal circuits can facilitate standing andstepping recovery in humans.

MicroFabricated High-Density Epidural Stimulating Arrays.

In various embodiments, the epidural electrical stimulation isadministered via a high density epidural stimulating array. In certainembodiments, the high density electrode arrays use microfabricationtechnology to place numerous electrodes in an array configuration on aflexible substrate. One suitable epidural array fabrication method wasfirst developed for retinal stimulating arrays (see, e.g., Maynard,Annu. Rev. Biomed. Eng., 3: 145-168 (2001); Weiland and Humayun, IEEEEng. Med. Biol. Mag., 24(5): 14-21 (2005)), and U.S. Patent Publications2006/0003090 and 2007/0142878 which are incorporated herein by referencefor all purposes (e.g., the devices and fabrication methods disclosedtherein). In various embodiments the stimulating arrays comprise one ormore biocompatible metals (e.g., gold, platinum, chromium, titanium,iridium, tungsten, and/or oxides and/or alloys thereof) disposed on aflexible material (e.g., parylene A, parylene C, parylene AM, paryleneF, parylene N, parylene D, or other flexible substrate materials).Parylene has the lowest water permeability of available microfabricationpolymers, is deposited in a uniquely conformal and uniform manner, haspreviously been classified by the FDA as a United States Pharmacopeia(USP) Class VI biocompatible material (enabling its use in chronicimplants) (Wolgemuth, Medical Device and Diagnostic Industry, 22(8):42-49 (2000)), and has flexibility characteristics (Young's modulus ˜4GPa (Rodger and Tai, IEEE Eng. Med. Biology, 24(5): 52-57 (2005))),lying in between those of PDMS (often considered too flexible) and mostpolyimides (often considered too stiff). Finally, the tear resistanceand elongation at break of parylene are both large, minimizing damage toelectrode arrays under surgical manipulation (Rodger et al., Sensors andActuators B-Chemical, 117(1): 107-114 (2006)).

The electrode array may be implanted using any of a number of methods(e.g., a laminectomy procedure) well known to those of skill in the art.

FIG. 3 shows a first prototype microelectrode array, scaled for mice, inwhich ten 250 micron diameter platinum electrodes are microfabricatedonto a 2 mm wide Parylene backing. The electrodes are dorsally implantedusing a laminectomy over the lumbosacral spinal cord, with one electrodeplaced over each intravertebral segment. In chronic implantation studies(using rat, mice, and pig animal models) of up to 6 months, we haveshown high biocompatibility of these arrays with mammalian tissue.Implantation of an array into a human subject is described in Example 1.

Of course, other microarray embodiments are contemplated. In certainembodiments, the number of electrodes formed on an electrode array canvary from one electrode to about 100,000 electrodes or more. In certainembodiments, the electrode microarray comprises at least 10, at least15, at least 20, at least 25, at least 50, at least 100, at least 250,at least 500, or at least 1000 electrodes. In various embodiments theinterelectrode spacing of adjacent electrodes in the electrode arrayvaries from about 100 μm or about 500 μm, or about 1000 μm or about 1500μm to about 2000 μm, or about 3000 μm, or about 4000 μm, or about 4500μm, or about 5000 μm. In various embodiments, interelectrode spakingranges from about 100 μm, about 150 μm, about 200 μm, or about 250 μm upto about 1,000 μm, about 2000 μm, about 3000 μm, or about 4,000 μm. Invarious illustrative embodiments, individual electrode diameters (orwidth) range from about 50 μm, 100 μm, 150 μm, 200 μm, or 250 μm up toabout 500 μm, about 1000 μm, about 1500 μm, or about 2000 μm.

The electrode array can be formed in any geometric shape such as asquare or circular shape; typically the size of the array will be on theorder of about 0.1 mm to about 2 cm, square or in diameter, depending inpart on the number of electrodes in the array. In various embodiments,the length of an electrode array ranges from about 0.01 mm, or 0.1 mm upto about 10 cm or greater.

In various embodiments, the arrays are operably linked to controlcircuitry that permits selection of electrode(s) to activate/stimulateand/or that controls frequency, and/or pulse width, and/or amplitude ofstimulation. In various embodiments, the electrode selection, frequency,amplitude, and pulse width are independently selectable, e.g., atdifferent times, different electrodes can be selected. At any time,different electrodes can provide different stimulation frequenciesand/or amplitudes. In various embodiments, different electrodes or allelectrodes can be operated in a monopolar mode and/or a bipolar mode,using constant current or constant voltage delivery of the stimulation.

In certain embodiments, the electrodes can also be provided withimplantable control circuitry and/or an implantable power source. Invarious embodiments, the implantable control circuitry can beprogrammed/reprogrammed by use of an external device (e.g., using ahandheld device that communicates with the control circuitry through theskin). The programming can be repeated as often as necessary.

FIG. 16 shows EMG responses from different muscle groups to differenttypes of stimulation (monopolor and bipolar) at different spinal sites.These data show that our strategy of spatially selective epiduralstimulation of different portions of the lumbosacral spinal cord canfocally excite and coordinate the muscle groups that are involved inlocomotion.

We have also developed and tested in rats more complex twenty-sevenelectrode arrays, which are arranged in a 9×3 pattern so that there are3 electrodes (mid-line, left, and right) at each of 9 intravertebralsegments (FIG. 7). These arrays have been tested for up to 6 weeks invivo, showing biocompatibility as well as stepping capability thatbetters the previous results we have obtained with conventionalelectrodes. FIG. 8 shows a 256 electrode array that was fabricated todemonstrate the potential for multi-layer fabrication technology tobuild an array of hundreds of electrodes.

Embodiments of the electrode arrays described herein may be constructedto offer numerous advantages. For example, flexible parylene electrodearrays are mechanically stable. Their flexibility allows them to conformto the contours of the spinal cord, forming a thin layer (e.g., 10 μmthick) that adheres to the cord. This close fit facilitates connectivetissue encapsulation, which also enhances fixation.

The arrays may also offer spatially selective stimulation. Early studiesof stimulation protocols to facilitate locomotion in SCI animalsdelivered stimuli to a single spinal cord region as the idealstimulation site was hypothesized to be fixed and species-specific.Researchers identified “optimal” stimulation sites for cats (Gerasimenkoet al., Neurosci. Behav. Physiol., 33(3): 247-254 (2003)) and for rats(Gerasimenko et al., J Neurosci. Meth., 157(2): 253-263 (2006)) at asingle time point after injury. However, the optimal stimulation sitemay not be constant. Rat studies showed that while stimulation at the L2spinal level facilitated the best stepping soon after a completetransection, S1 stimulation produced more effective stepping severalweeks later (Id.). Similarly, clinical data from patients receiving SCSfor the treatment of lower back pain indicates that continued painsuppression often requires adjustment of the electrode position (Carter,Anaesth. Intensive Care, 32(1): 11-21 (2004)). These data support thehypothesis that the optimal stimulation pattern is not fixed. After atraumatic injury, the spinal cord is continuously modified by theprogression of secondary damage, as well as the post-injury therapies.Our arrays' high electrode density enables ongoing identification of theoptimal stimulation patterns. Our arrays' high-density allows adjustmentof the stimulating pattern to account for migration, or for initialsurgical misalignment.

The electrode arrays described herein also facilitate the use ofadvanced stimulation paradigms. Given the complex chain of reflexesinvolved, for example, in stepping, we believe that more sophisticatedspatiotemporal stimulation patterns, involving either simultaneous orsequential stimulation of different spinal cord regions, may facilitateimproved posture and locomotion and reaching and grasping compared withsimple patterns. The high electrode densities allow us to test advancedstimulation paradigms that have previously been infeasible to study.

In addition, the electrode arrays provide for a lower charge injectionamplitude and lower power consumption. The close positioning to thespinal cord possible with electrode arrays described herein minimizesthe required levels of charge injection and power consumption. Sincelong-term tissue damage caused by electrical stimulation is proportionalto injected charge, our conformal arrays allow longer sustained bouts ofstimulation. This is desirable for long-term stimulation therapy and forbattery-powered implants.

The electrode arrays described herein facilitate the measurement andevaluation of evoked potentials. Our electrode arrays can record fieldpotentials from the dorsum (or other regions) of the spinal cord. Spinalsomatosensory evoked potentials (SSEPs) measured from different levelsof the spinal cord can be used to assess the state of the spinal cordand, potentially, to identify and classify the nature of a spinalinjury. SSEPs are typically composed of a series of responses. With anarray, response latency, amplitude, and conduction velocity can besimultaneously gathered from positions throughout the lumbosacral spinalcord. Examining the SSEPs for different injury types facilitates thegeneration of an injury-specific atlas of spinal potentials. SSEPs canbe used as a measure of recovery and to evaluate the potentialeffectiveness of different treatment paradigms that might be applied.Monitoring SSEPs at different time points after the start of a treatmentprovides insight into the synaptic mechanisms that are involved inreacquiring locomotor function, and also serve as a diagnostic of howand if a particular strategy is aiding recovery. For example, recentdata collected in our lab suggests that the return of polysynapticspinal responses may be correlated with regaining the ability to step.

Use of Machine Learning to Select Optimal Electrode Array StimulationParameters

High density epidural stimulating electrode arrays can providepatient-customized stimuli, compensate for errors in surgical placementof the array, and adapt the stimuli over time to spinal plasticity(changes in spinal cord function and connectivity). However, with thisflexibility comes the burden of finding suitable stimuli parameters(e.g., the pattern of electrode array stimulating voltage amplitudes,stimulating currents, stimulating frequencies, and stimulating waveformshapes) within the vast space of possible electrode array operatingpatterns. It is not practical to exhaustively test all possibleparameters within this huge space to find optimal parametercombinations. Such a process would consume a large amount of clinicalresources. A machine learning algorithm can employed to more efficientlysearch for effective parameter combinations. Over time, a machinelearning algorithm can also be used to continually, occasionally, and/orperiodically adapt the stimulation operating parameters as needed.

A machine learning algorithm that seeks to optimize the stimuliparameters desirably alternates between exploration (searching theparameter space and building a regression model that relates stimulusand motor response) and exploitation (optimizing the stimuli patternsbased on the current regression model). Many machine learning algorithmsincorporate exploration and exploitation phases, and any learningalgorithm that incorporates these two phases can be employed as aprocedure to select (e.g., optimize) the electrode array stimulatingparameters over time.

One particular embodiment relies upon Gaussian Process Optimization(GPO) (Rasmussen, Gaussian Processes for Machine Learning, MIT Press(2006)), an active learning method whose update rule explores andexploits the space of possible stimulus parameters while constructing anonline regression model of the underlying mapping from stimuli to motorperformance (e.g., stepping, standing, or arm reaching). GaussianProcess Regression (GPR), the regression modeling technique at the coreof GPO, is well suited to online use because it requires fairly minimalcomputation to incorporate each new data point, rather than theextensive recomputation of many other machine learning regression ofmodels lying within a restricted set, rather than from a single model,allowing it to avoid the over-fitting difficulties inherent in manyparametric regression and machine learning methods.

GPR is formulated around a kernel function, k(,), that can incorporateprior knowledge about the local shape of the performance function(obtained from experience and data derived in previous epiduralstimulation studies), to extend inference from previously exploredstimulus patterns to new untested stimuli. Given a function thatmeasures performance (e.g., stepping, standing, or reaching), GPO isbased on two key formulae and the selection of an appropriate kernelfunction. The core GPO equation describes the predicted mean μ_(t)(x*)and σ_(t) ²(x*) of the performance function (over the space of possiblestimuli), at candidate stimuli x*, on the basis of past measurements(tests of stimuli values X={x₁, x₂, . . . } which returned noisyperformance values Y_(t)={y₁, y₂, . . . })

μ_(t)(x*)=k(x*,X)[K _(t)(X,X)+σ_(n) ² I] ⁻¹ Y _(t);

σ_(t) ² =k(x*,x*)−k(x*,X)[K _(t)(X,X)+σ_(n) ² I] ⁻¹ k(X,x*)

where K_(t) is the noiseless covariance matrix of past data, and σ_(n) ²is the estimated noise covariance of the data that is used in theperformance evaluation. To balance exploration of regions of the stimulispace where little is known about expected performance with exploitationof regions where we expect good performance, GPO uses an upperconfidence bound update rule (Srinivas and Krause, Gaussian ProcessOptimization in the bandit setting: No Regret and Experimental Design,Proc. Conf. on Machine Learning, Haifa Israel (2010)).

x ₁=argmax_(KCx)·[μ_(t)(x)+β_(t)σ_(t)(x)].

When the parameter β_(t) increase with time, and if the performancefunction is a Gaussian process or has a low Reproducing Kernel HilbertSpace norm relative to a Gaussian process, GPO converges with highprobability to the optimal action, given sufficient time.

The definition of a performance function that characterizes human motorbehavior (e.g. standing or stepping behavior) typically depends upon twofactors: (1) what kinds of motor performance data is available (e.g.,video-based motion capture data, foot pressure distributions,accelerometers, electromyographic (EMG) measurements, etc.); and (2) theability to quantify motor performance. While more sensory data ispreferable, a machine learning approach to parameter optimization canemploy various types of sensory data related to motor performance. Itshould be noted that even experts have great difficulty determiningstepping or standing quality from such data without also looking atvideo or the actual subject as they undertake a motor task. However,given a sufficient number of training examples from past experiments andhuman grading of the standing or stepping in those experiments, a set offeatures that characterize performance (with respect to the given set ofavailable sensors) can be learned and then used to construct areasonable performance model that captures expert knowledge and thatuses the available measurement data.

FIGS. 18A-18B depict a multi-compartment physical model of theelectrical properties of mammalian spinal cord, along with a 27electrode array placed in an epidural position. FIGS. 18A-18B also showthe isopotential contours of the stimulating electric field for the2-electrode stimulation example. FIG. 19 shows the instantaneous andaverage “regret” (a measure of the error in the learning algorithmssearch for optimal stimuli parameters) when the Gaussian ProcessOptimization algorithm summarized above is used to optimize the arraystimulus pattern that excites neurons in the dorsal roots betweensegments L2 and S2 in the simulated spinal cord. The instantaneousregret performance shows that the learning algorithm rapidly findsbetter stimulating parameters, but also continually explores thestimulation space (the “bursts” in the graph of instantaneous regretcorrespond to excursions of the learning algorithm to regions ofstimulus parameter space which were previously unknown, but which havebeen found to have poor performance).

Use of Robotically Guided Training to Assist Recovery of Standing andStepping.

FIG. 2 shows that the use of physical training in combination withepidural stimulation and drug therapy produces better stepping behavior.Similarly, Example 1, herein, shows a similar effect of the combinationof epidural stimulation and physical training/loading in a humansubject.

While such physical manipulation can be facilitated by the use oftrainers, e.g., as described above and in Example 1, in certainembodiments, the use of robotic devices and novel robotic controlalgorithms to guide and monitor the physical training process iscontemplated. Robotic devices have been used successfully to trainstepping and standing in complete spinal cord injured laboratory animals(Fong et al., J Neuroscience, 25(50): 11738-11747 (2005); de Leon etal., Brain Res Brain Res Rev., 40(1-3): 267-273 (2002); de Leon et al.,J Neurophysiol., 182(1): 359-369 (1999)). However, recovery of effectivepatterns and levels of neuromuscular activity in humans with SCI(without epidural stimulation) as a result of training with a roboticdevice has not yet been as successful (Wernig, Arch Phys Med Rehabil.,86(12): 2385-2386 (2005); author reply 2386-2387).

It is contemplated that “assist-as-needed” control algorithms that mimicthe behavior of human therapists during weight supported treadmill steptraining of human SCI patients can be utilized. When the limb kinematicsof the SCI patient are poor, the therapists provides a large amount ofphysical bias to force the limbs to follow a more normal steppingpattern, as well as cutaneous sensory input to trigger reflex responses.When the limbs are moving close to a normal stepping pattern, thetherapist provides little physical bias or sensory input to the patient.We implemented these algorithms on the robot of FIG. 9, and found thateven primitive assist-as-needed algorithms provide significantimprovement in the rate and quality of step recovery. In this roboticdevice, lightweight low-friction robot arms guide the motions of theankles of a weight-supported spinalized animal (mouse or rat) as itsteps at various speeds on the moving treadmill. Because of the arms'low mass, they can also be used in a passive mode for testing locomotionability—the movements of the animal's ankles are recorded by the robotas it attempts to walk on the treadmill (see, e.g., Cai, et al., Proc.Int. Conference Rehab. Robotics., 9: 575-579 (2005)).

Pharmacological Facilitation of Stepping, Standing, Reaching andGrasping.

In certain embodiments, the methods described herein are used inconjunction with various pharmacological agents. In particular, the useof various serotonergic, and/or dopaminergic, and/or noradrenergicand/or GABAergic, and/or glycinergic drugs, particularly drugs that havebeen demonstrated to be effective in facilitating stepping in animals iscontemplated. These agents can be used in combination with epiduralstimulation and physical therapy as described above. This combinedapproach can help to put the spinal cord (below the site of lesion) inan optimal physiological state for controlling a range of lower andupper limb movements.

In certain embodiments, the drugs are administered systemically, whilein other embodiments, the drugs are administered locally, e.g., toparticular regions of the spinal cord. Drugs that modulate theexcitability of the spinal neuromotor networks are combinations ofnoradrenergic, serotonergic, GABAergic, and glycinergic receptoragonists and antagonists. Illustrative pharmacological agents include,but are not limited to agonists and antagonists to one or morecombinations of serotonergic: 5-HT1A, 5-HT2A, 5-HT3, and 5HT7 receptors;to noradrenergic alpha1 and 2 receptors; and to dopaminergic D1 and D2receptors (see, e.g., Table 1).

TABLE 1 Illustrative pharmacological agents. Optimal Concen- Range oftration tested con- (mg/ centrations Name Target Action Route Kg)(mg/Kg) Serotonergic receptor systems 8-OHDPAT 5-HT1A7 Agonist S.C. 0.050.045-0.3  Way 100.635 5-HT1A Antagonist I.P. 0.5 0.4-1.5 Quipazine5-HT2A/C Agonist I.P. 0.2 0.18-0.6  Ketanserin 5-HT2A/C Antagonist I.P.3 1.5-6.0 SR 57227A 5-HT3 Agonist I.P. 1.5 1.3-1.7 Ondanesetron 5-HT3Antagonist I.P. 3 1.4-7.0 SB 269970 5-HT7 Antagonist I.P. 7  2.0-10.0Noradrenergic receptor systems Methoxamine Alpha1 Agonist I.P. 2.51.5-4.5 Prazosin Alpha1 Antagonist I.P. 3 1.8-3.0 Clonidine Alpha2Agonist I.P. 0.5 0.2-1.5 Yohimbine Alpha2 Antagonist I.P. 0.4 0.3-0.6Dopaminergic receptor systems SKF-81297 D1-like Agonist I.P. 0.20.15-0.6  SCH-23390 D1-like Antagonist I.P. 0.15  0.1-0.75 QuinpiroleD2-like Agonist I.P. 0.3 0.15-0.3  Eticlopride D2-like Antagonist I.P.1.8 0.9-1.8

The foregoing embodiments are intended to be illustrative and notlimiting. Using the teachings and examples provided herein, numerousvariations on the methods and devices described herein will be availableto one of ordinary skill in the art.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1 Epidural Stimulation of the Lumbosacral Spinal Cord EnablesIndependent Standing, Voluntary Movement, and Assisted Stepping in aParaplegic Human

This example demonstrates that the human spinal cord circuitry has theability to generate postural and locomotor patterns without supraspinalmotor input. This capability and voluntary movement can be manifestedwhen the excitability of these networks is modulated by epiduralstimulation at a level that enables proprioceptive input to provide asource of neural control to elicit the motor pattern appropriate for thetask.

Introduction

The mammalian spinal cord can generate locomotor output in the absenceof input from the brain. See Grillner S., Neurobiological bases ofrhythmic motor acts in vertebrates, Science, 228:143-149 (1985); andRossignol S, Barriere G, Frigon A, Barthelemy D, Bouyer L, Provencher J,et al., Plasticity of locomotor sensorimotor interactions afterperipheral and/or spinal lesions, Brain Res Rev, 57(1):228-240 (January2008). This capability has been attributed to the phenomenon of centralpattern generation. See Grillner S, Wallen Peter, Central patterngenerators for locomotion, with special reference to vertebrates, AnnRev Neurosci, 8:233-261 (1985); and Grillner S, Zangger P., On thecentral generation of locomotion in the low spinal cat, Exp Brain Res,34:241-261 (1979). Functional standing and stepping can be executed bycats with complete transection of the spinal cord when sensory input isprovided to the lumbosacral locomotor pattern generator circuitry. Seede Leon R D, Hodgson J A, Roy R R, Edgerton V R., Locomotor capacityattributable to step training versus spontaneous recovery afterspinalization in adult cats, J Neurophysiol, 79:1329-1340 (1998); andBarbeau H, and Rossignol S., Recovery of locomotion after chronicspinalization in the adult cat, Brain Res, 412:84-95 (1987). Spinal catscan learn to stand, fully supporting their hindquarters, and to stepover a range of speeds and load-bearing levels with task specifictraining. Adult spinally transected rats, unlike cats, can generatestepping only with additional combined interventions of locomotortraining, pharmacological intervention, and/or epidural stimulation. SeeCourtine G, Gerasimenko Y, van den BR, Yew A, Musienko P, Zhong H, etal., Transformation of nonfunctional spinal circuits into functionalstates after the loss of brain input, Nat Neurosci, 12(10):1333-1342(October 2009); and Ichiyama R M, Courtine G, Gerasimenko Y P, Yang G J,van den BR, Lavrov I A, et al., Step training reinforces specific spinallocomotor circuitry in adult spinal rats, J Neurosci, 16;28(29):7370-7375 (July 2008). These observations demonstrate a level ofautomaticity sufficient to generate locomotion without any supraspinalinfluence. This evidence leads to the hypothesis that if similar spinalcircuits exist in humans then electrically stimulating the lumbosacralspinal cord epidurally should be able to facilitate standing andstepping in an individual with a motor complete spinal cord injury.

Although, rhythmic motor patterns of the legs have been observed, 12-15sustained independent, full weight-bearing standing and stepping has notbeen reported in humans after complete motor paralysis. See Calancie B.,Spinal myoclonus after spinal cord injury, J Spinal Cord Med, 29:413-424(2006); Dimitrijevic M R, Gerasimenko Y, Pinter M M, Evidence for aspinal central pattern generator in humans, Ann NY Acad Sci, 16;860:360-376 (November 1998); Kuhn R A. Functional capacity of theisolated human spinal cord, Brain, 73(1):1-51 (1950); and Nadeau S,Jacquemin G, Fournier C, Lamarre Y, Rossignol S., Spontaneous motorrhythms of the back and legs in a patient with a complete spinal cordtransection, Neurorehabil Neural Repair, 24(4):377-383 (May 2010).However, after a motor incomplete SCI functional improvements occur withintense locomotor training and with epidural stimulation. See Wemig A,and Muller S., Laufband locomotion with body weight support improvedwalking in persons with severe spinal cord injuries, Para; 30:229-238(1992); Wemig A, Nanassy A, Muller S., Maintenance of locomotorabilities following Laufband (treadmill) therapy in para- andtetraplegic persons: follow-up studies, Spinal Cord, 36:744-749 (1998);and Herman R, He J, D'Luzansky S, Willis W, Dilli S., Spinal cordstimulation facilitates functional walking in a chronic, incompletespinal cord injured. Spinal Cord, 40(2):65-68 (February 2002). Rhythmicefferent activity timed to the step cycle, however, can occur duringmanually facilitated stepping and bilateral tonic activity can occurduring partial weight bearing standing in individuals with a clinicallycomplete SCI after extensive task specific training. See Dietz V,Colombo G, Jensen L., Locomotor activity in spinal man, The Lancet,344:1260-1263 (1994); Harkema S J, Hurley S L, Patel U K, Requejo P S,Dobkin B H, Edgerton V R, Human lumbosacral spinal cord interpretsloading during stepping, J Neurophysiol, 77(2):797-811 (1997); andHarkema S J, Plasticity of interneuronal networks of the functionallyisolated human spinal cord, Brain Res Rev, 57(1):255-264 (January 2008).Rhythmic and tonic motor patterns of the legs have been induced viaepidural stimulation in humans after motor complete SCI while lyingsupine. See Dimitrijevic M R, Gerasimenko Y, Pinter M M, Evidence for aspinal central pattern generator in humans, Ann NY Acad Sci, 16;860:360-376 (November 1998); Gerasimenko Y, Daniel 0, Regnaux J,Combeaud M, Bussel B., Mechanisms of locomotor activity generation underepidural spinal cord stimulation, In: Dengler R, Kossev A, editors,Washington, D.C.: 105 Press, p. 164-171 (2001); and Minassian K, JilgeB, Rattay F, Pinter M M, Binder H, Gerstenbrand F, et al., Stepping-likemovements in humans with complete spinal cord injury induced by epiduralstimulation of the lumbar cord: electromyographic study of compoundmuscle action potentials, Spinal Cord, 42(7):401-416 (July 2004). Thissuggests that spinal circuitry for locomotion is present in the humanbut cannot functionally execute these tasks without some level ofexcitability from supraspinal centers that may be present afterincomplete SCI.

We hypothesized that tonic epidural spinal cord stimulation can modulatethe human spinal circuitry into a physiological state that enablessensory input derived from standing and stepping movements to serve as asource of neural control to perform these tasks. We observed that thespinal circuitry was able to generate independent standing in responseto task specific sensory cues in the presence of epidural stimulation ina paraplegic subject with a motor complete spinal cord injury.Stepping-like patterns were also generated with epidural stimulationwith the subject on a treadmill using body weight support and manualfacilitation. The subject also regained some voluntary control of thelegs seven months post implantation. We have used epidural stimulationto substitute for descending signals that normally come from the brainto modulate the physiological state of the spinal networks and thesensory information can be used as a source of neural control of themotor task. Unexpectedly, clinical assessments indicated improvements inother physiological functions including bladder, sexual function andtemperature regulation.

Methods Clinical Characteristics Prior to Implantation

The subject is a 23 year old man who had been struck by a motor vehicle3.4 years prior to implantation. He sustained a C7-T1 subluxation withinjury to the lower cervical and upper thoracic spinal cord.Neurological examination revealed paraplegia. The triceps and intrinsichand muscles exhibited voluntary contraction but were weak. He had nocontraction of trunk or leg muscles. He was treated emergently withreduction of the subluxation by anterior interbody fusion andinstrumentation. Magnetic resonance imaging of the injury site obtainedprior to implantation revealed myelomalacia and atrophy of the cordsegment adjacent to the T1 vertebral body (see FIG. 10A).

Prior to the lumbosacral epidural implantation his neurological deficitwas classified using the American Spinal Injury Association (ASIA)impairment scale (AIS) as ASIA B (pinprick and light-touch present belowthe lesion). Marino R J, Barros T, Biering-Sorensen F, Bums S P, DonovanW H, Graves D E, et al., International standards for neurologicalclassification of spinal cord injury, J Spinal Cord Med, 26 Suppl1:S50-S56 (2003). He had no motor function of trunk or leg muscles, aflaccid anal sphincter, and no voluntary bladder contraction (see FIG.10B). Sensation was abnormal below C7.

Somatosensory evoked potentials showed bilateral delay of corticalresponses from posterior tibial nerve stimulation. Latencies of sensoryevoked potentials recorded at Erb's point, cervical, and contralateralcortical sites in response to median nerve stimulation at the wrist werewithin normal ranges. Lower extremity nerve conduction studies werenormal. No response was elicited from leg muscles by transcranialmagnetic stimulation of the motor cortex using a butterfly coil centeredover Cz. He was unable to stand or walk independently or voluntarilymove his legs despite standard-of-care rehabilitation and additionalintensive locomotor training.

The research subject signed an informed consent for electrodeimplantation, stimulation, and physiological monitoring studies that wasapproved by the University of Louisville and the University ofCalifornia, Los Angeles Institutional Review Boards. To be certain therewas no remaining potential for standing and walking, prior to theelectrode implantation, the participant received 170 locomotor trainingsessions over a period of 26 months using body weight support on atreadmill with manual facilitation resulting in 108 hours of steptraining and 54 hours of stand training with no detectable change in EMGactivity (see FIG. 12). During standing, throughout training noobservable EMG was evident. During assisted stepping, sporadic EMGactivity was observed in the lower leg muscles, most often in the medialhamstrings, however, was never observed EMG activity in all musclesbilaterally. No detectable improvement in EMG was noted over the courseof the training.

Surgical Implantation of Electrode Array and Stimulator

An epidural spinal cord stimulation unit (Medtronics, Restore Advanced)was used to electrically stimulate the lumbar-sacral enlargement. A16-electrode array was implanted epidurally under fluoroscopic controlat T11-L1 over lumbosacral spinal cord segments L1-S1 (see FIG. 11A).The location of the electrode array was evaluated and adjusted duringsurgery with fluoroscopy and electrophysiologically with EMG recordedfrom leg muscles. See Murg M, Binder H, Dimitrijevic M R, Epiduralelectric stimulation of posterior structures of the human lumbar spinalcord: 1. muscle twitches—a functional method to define the site ofstimulation, Spinal Cord, 38:394-402 (2000). EMG responses were elicitedby epidural stimulation at 2 Hz during a sequence of increasing voltagesand specific electrode configurations to determine threshold of muscleactivation and amplitude of the response. A midline stimulationconfiguration was followed using one cathode and one anode electrode,with each electrode pair being 6 mm apart. Multiple stimulationcombinations were performed ranging from most rostral to most caudalpositions. Symmetry was also tested by using left and right sideelectrodes within the array. The electrode lead was tunneled to asubcutaneous abdominal pouch where the pulse generator was implanted.Two weeks after implantation the position of the array was reconfirmedwith the subject lying supine using the same stimulation protocols (seeFIGS. 11C-11D).

Experimental Design

Stimulation parameters were systematically evaluated to identify theoptimal stimulation parameters for generating efferent patterns forstanding and stepping. Stimulation of the spinal cord was carried outduring sessions lasting up to 250 minutes in which physiologicalparameters were measured. The total duration of stimulation during eachexperimental session ranged from 40 minutes to 120 minutes. Stimulationamplitudes ranged from 0.5 V to 10.0 V and stimulation frequencies from5 to 40 Hz using either a 210 or 450 μs pulse width. The optimalconfigurations for standing were those with which sustainable tonicco-activation were evoked; for stepping optimal configurations werethose in which rhythmic activity was present with alternation of rightand left leg and intralimb flexors and extensors. EMG activity of 14lower extremity muscles and hip, knee, and ankle joint angles weremeasured.

During experimental sessions on the treadmill, level of body weightsupport (Innoventor, St. Louis, Mo.) and amount of body weight load werealso measured. Trainers provided manual facilitation, when needed,distal to the patella during the stance phase, and at the poplitealfossa and anterior distal tibia for foot clearance during the swingphase and at the pelvis for stabilization and weight shifting duringstepping. Stand training was performed using a custom-made standingdevice designed to provide full weight-bearing and pelvis support. Thedevice included vertical and horizontal bars positioned about (orsurrounding) the subject to allow him to assist balance. Bungees wereattached to the device to provide support only if the knees or hipsflexed beyond the normal standing posture. The total duration ofstimulation during each session averaged 44 minutes (sessions 1-34) and60 minutes (sessions 35-80). Epidural stimulation was not providedoutside laboratory sessions. The subject attempted to stand for 60minutes during each training session. To optimize independent standingstimulation parameters (electrode configuration, voltage and frequency)were modified approximately once per week.

During sitting, stimulation voltage was increased to a desired level.This voltage was kept constant as the subject went from sitting tostanding and throughout the standing bout. The subject initiated the sitto stand transition by positioning his feet shoulder width apart andshifting his weight forward to begin loading the legs. The subject usedthe bars of the standing device during the transition phase to balanceand to partially pull himself into a standing position. Trainerspositioned at the pelvis and knees assisted as needed during the sit tostand transition. Elastic bungees posterior to the pelvis were set byone of the trainers after the subject achieved full-weight bearingstanding. These bungees helped the subject sustain appropriate pelvictilt and position and allowed him to safely stand with minimalassistance.

During the standing bout, one trainer assisted the subject by applyingposteriorly directed gentle pressure at the patellar tendon as necessaryto maintain knee extension. The subject was encouraged to stand for aslong as possible throughout the session.

Seated resting periods occurred when requested by the subject andreduced in frequency and duration as the training progressed. Nostimulation was provided during the rest periods.

During the first stand session, the subject required 7 breaks (standtime: 60 min; rest time 67 minutes). By session 35, the subject was ableto stand for 1 bout lasting a full 60 minutes. The total duration ofstimulation averaged across all sessions was 54±13 minutes per session.

Data Acquisition

EMG, joint angles, footswitch, ground reaction forces and BWS data werecollected at 2,000 Hz using a 32-channel hard-wired AD board andcustom-written acquisition software (National Instruments, Austin,Tex.). Bilateral EMG (Motion Lab Systems, Baton Rouge, La.) from thesoleus, medial gastrocnemius, tibialis anterior, medial hamstrings,quadriceps, and gluteus maximus muscles was recorded using bipolarsurface electrodes with fixed inter-electrode distance. Harkema S J,Hurley S L, Patel U K, Requejo P S, Dobkin B H, Edgerton V R, Humanlumbosacral spinal cord interprets loading during stepping, JNeurophysiol, 77(2):797-811 (1997); and Beres-Jones J A, Johnson T D,Harkema S J, Clonus after human spinal cord injury cannot be attributedsolely to recurrent muscle-tendon stretch, Exp Brain Res, 149(2):222-236(March 2003). Bilateral EMG from the iliopsoas was recorded withfine-wire electrodes. Two surface electrodes placed symmetricallylateral to the electrode array incision site over the paraspinal muscleswere used to record the stimulation artifact. Hip, knee, and ankle jointangles were acquired using a high speed passive marker motion capturesystem (Motion Analysis, Santa Rosa, Calif.). Ground reaction forceswere collected using shoe-insole pressure sensors FSCAN or HRMAT(TEKSCAN, Boston, Mass.).

Results

The patient was always aware when the stimulation was on, with the mostcommon sensation being a tingling feeling localized to the thoracolumbarelectrode implantation site. There was a similar sensation in thosemuscles that were targeted for activation. Parasthesias were alsoroutinely perceived in the trunk, hips, and legs and varied according tothe intensity of stimulation, however were never at a level thatproduced discomfort or pain and never precluded the use of epiduralstimulation.

EMG Activity with Epidural Stimulation for Standing

Epidural stimulation at 15 Hz and 8 V of the caudal segments (L5-S1) ofthe spinal cord combined with sensory information related to bilateralextension and loading was sufficient to generate standing on day five ofstimulation (see FIG. 13). Standing without manual facilitation at thelegs was achieved using stimulation (15 Hz, 8 V) with 65% body weightsupport (see FIG. 13, panel A). The subject was able to sustain standingwithout any manual facilitation while the level of body weight supportwas progressively reduced to full weight-bearing (see FIG. 13, panel B).

Transitioning from sitting to standing without body weight supportaltered the EMG activity during rostral or caudal epidural stimulationeven though the parameters remained constant (see FIG. 14). When loadingof the legs was initiated, the EMG activity increased dramatically andwas sufficient to support the subject's body weight with minimalassistance required by the trainers. During this transition, thestimulation remained constant using the same location, frequency, andintensity parameters (FIG. 14, panels B-E). The EMG activity was alsomodulated by the site and intensity of stimulation. The EMG activity wasdependent on the site and intensity of stimulation with the caudal(L5-S1) stimulation at higher intensities resulting in the most optimalmotor pattern for standing (see FIG. 14, panels A-C). During caudalstimulation, there was a more dramatic increase in the EMG amplitudebilaterally in the more proximal muscles while EMG of the more distalmuscles was initially markedly reduced (see FIG. 14, panels C and E).Once standing was achieved, there was more co-contraction of bothflexors and extensors and proximal and distal muscles with stimulation.

Postural Responses and Independent Standing with Epidural Stimulation

Postural responses were observed in the leg EMG activity when thesubject voluntarily shifted his center of gravity sagittally whilestanding with epidural stimulation and intermittent manual assistance(see FIG. 15, panel A). The EMG burst of the medial gastrocnemiusincreased with forward deviation, whereas backward deviation induced EMGbursts in the tibialis anterior. Independent standing bouts with tonicbilateral EMG activity routinely occurred for several continuous minutesand increased in frequency and duration as stand training progressed(see FIG. 15, panel B). After 80 sessions, the subject could initiateand maintain continuous independent standing (maximum 4.25 min) withbilateral tonic EMG activity (see FIG. 15, panel B). Oscillatorypatterns, often clonic-like, emerged during the latter part of theperiods of independent standing and then were followed by little or noEMG activity that corresponded with the loss of independence (requiringa return to manually facilitated standing). These periods of independentstanding were repeated during the 60-minute standing sessions.

Thus, independent standing occurred when using stimulation havingparameters selected (e.g., optimized) to facilitate standing whileproviding bilateral load-bearing proprioceptive input.

Locomotor Patterns with Epidural Stimulation

For stepping, epidural stimulation at 30-40 Hz and task-specific sensorycues were used to generate locomotor-like patterns. Sensory cues frommanually facilitated stepping included load alternation and legpositioning with appropriate kinematics of the hips, knees, and anklestimed to the step cycle. Stepping with BWST without epidural stimulationproduced little or no EMG activity (see FIG. 16, panel A). Stepping withBWST and manual facilitation in conjunction with caudal epiduralstimulation resulted in an oscillatory EMG pattern in flexors andextensors (see FIG. 16, panel B). The afferent feedback determined themotor efferent pattern (see FIG. 16, panels C and D). The EMG activityin the legs was dramatically different depending on the loading andkinematic patterns when using the identical stimulation parameters.Oscillatory EMG patterns were evident only when alternating loading andflexion and extension of the lower limbs occurred (see FIG. 16, panels Cand D).

Voluntary Control of Leg Movement

Voluntary (or supraspinal) control of the toe extension, ankleflexation, and leg flexion emerged only in the presence of epiduralstimulation (see FIG. 17) seven months after the epidural implant thatincluded 80 stand training sessions with epidural stimulation. Voluntarymovement was observed in both limbs. However, the epidural stimulationparameters were different for each leg and technical limitations of thestimulator prevented simultaneous movements of the legs bilaterally.When the subject was instructed to flex (draw the leg upward) the toeextended, the ankle dorsi-flexed and the hip and knee flexed with theappropriate muscle activation. When instructed to dorsi-flex the ankle,the foot moved upward with tibialis anterior activation. When instructedto extend the great toe, the toe moved upward with activation of theextensor hallicus longus. For each task, the muscle activation wasspecific for the movement and the timing of activation was closelylinked to the verbal commands (see FIGS. 17C-17E). The subject couldconsciously activate the appropriate muscles for the intended movement,and the timing of activation was closely linked to the verbal commands(see FIG. 17E). The ability to selectively activate different motorpools demonstrates an important feature of voluntary motor control.

Thus, locomotor-like patterns were observed when stimulation parameterswere selected (e.g., optimized) to facilitate stepping. Further, sevenmonths after implantation, the subject recovered supraspinal control ofcertain leg movements, but only during epidural stimulation.

Subject's Perspective

Given the uniqueness of the epidural stimulation procedures and theunusual level of commitment of the subject to the objectives of thestudy, the research team asked the subject his perspective on a range ofhighly personal topics related to changes in his health and daily livingafter compared to before the implant.

Interpretation of these responses should take into account that thesubject received extensive rehabilitation for 170 sessions immediatelybefore the implant. Specifically, the subject provided the followingresponses as to how (other than demanding so much of his time) theexperience affected the specified aspect of his life:

1. sleep patterns: I am sleeping more soundly, and am able to reach adeeper level of sleep (the dream phase) almost every night. I have alsonoticed that I need more sleep, at least 10 hours a night and sometimesmore after a hard or draining workout.

2. daily activity patterns: Besides the issue of being tired from theworkouts, I have had more over all energy. I have been more activeduring the days than before the implant. This has improved since thefirst few workouts after the surgery, since at first I could not doanything and even had trouble transferring after workouts, but this hascontinuously gotten better every day.

3. bladder or bowel function: In terms of my bladder, I've been able toempty more often on my own, on command, without a catheter. So far I'vehad no infections as well. In terms of my bowel function, I'm moreregular.

4. sensory function: I've been able to feel more sharp and dullsensations in places where I wasn't able to before the surgery, such asthrough my stomach and legs. Also I'm having better sensation with lighttouch throughout my midsection and legs. Refer to most recent ASIA examwhere I had mostly zeros before surgery and now have mostly ones.

5. severity and frequency and timing of spasticity: My spasticity hasincreased only when lying down.

6. frequency and kind of medical care needed: Other than when mystitches opened shortly after surgery no medical care has been neededsince surgery.

7. sexual function: Erections have been stronger and more frequent and Iam able to reach full orgasm occasionally. I had never before been ableto do this before the surgery.

8. diet, appetite: I feel like I get hungrier after working out, butother than that no change.

9. body weight: I've gained about 9 kilograms since surgery.

10. observable changes in muscle: My leg muscles have increased by a fewinches and I am able to see definition in my quads and calfs. My upperbody (biceps, triceps, shoulders etc.) have also gained inches of muscleand I have not lifted a weight since surgery. My overall core has gottenstronger and more stable.

11. posture and stability when sitting: My posture has improved. I'mmore stable and have less need to hold onto things to support myself.

12. skin lesions or sensitivity to infections: I have had no infectionsor skin lesions.

13. other functions: I feel healthier, I have better self-esteem andconfidence. My legs are heavier and more dense.

Clinical Impressions

With training and epidural stimulation, the subject had functional gainsin bladder and sexual function, and temperature regulation. The subjecthas been able to voluntarily void with minimal residual volume, andreports normal sexual response and performance. The subject regaineddiaphoretic capability and ability to tolerate temperature extremes. Inaddition, a sense of well-being and increased self-esteem enabled morefrequent social interactions. An eighteen percent gain in weight wasassociated with increased appetite and relative increase in lean bodymass and decrease in total body fat as measured using aq DEXA scan.

Discussion

We have used an epidurally implanted electrode array to modulate thephysiological state of the spinal circuitry to enable independentstanding in a human with a chronic motor complete spinal cord injury.The epidural stimulation did not induce standing by directly activatingmotor pools, but enabled motor function by engaging populations ofinterneurons that integrated load-bearing related proprioceptive inputto coordinate motor pool activity. This phenomenon was observed withinthe first week of stimulation. Although motor pool activity occurred inthe presence of epidural stimulation during sitting, the functionalactivity needed for standing required the proprioceptive informationassociated with load bearing positional changes. Dynamic changes inposition during standing were accompanied by motor patterns needed tomaintain upright posture without changes in the epidural stimulationparameters. Intensive task specific training combined with epiduralstimulation extended the duration of periods of independent standingthat could be initiated by the subject.

Robust, consistent rhythmic stepping-like activity emerged duringstepping only when tonic epidural stimulation and weight-bearingassociated proprioception was present. When standing, the same epiduralstimulation parameters elicited primarily tonic bilateral activity;however when stepping it resulted in rhythmic alternating activity.Without being limited by theory, it is believed the epidural stimulationmay activate dorsal root afferent fibers and, more likely at higherintensities, dorsal columns and additional spinal structures. Thecontinuous stimulation enabled the spinal cord to process the sensoryinformation that is closely linked to the desired functional task bymodulating the physiological state of the spinal cord. This is of greatclinical importance and it allows the intervention to become feasiblesince the task needed can be driven and controlled by intrinsicproperties of the nervous system rather than an external control system.

Our study demonstrates that the sensory input can serve as thecontroller of the spinal circuitry during independent standing andassisted stepping when enabled by epidural stimulation in the absence ofsupraspinal input in humans.

The present results show that movements of several lower limb joints canbe controlled voluntarily. In subjects with a motor incomplete spinalinjury, a common phenomenon is the general loss of specificity ofcontrol of selected muscles, however, the voluntary nature of thesereported movements are selective. See Maegele M, Muller S, Wernig A,Edgerton V R, Harkema S J, Recruitment of spinal motor pools duringvoluntary movements versus stepping after human spinal cord injury, JNeurotrauma, 19(10):1217-1229 (October 2002). In Example 1, theactivated motor pools were appropriate for the intended movement. Twopossible mechanisms that might explain this result include: 1) that theepidural stimulation provided excitation of lumbosacral interneurons andmotoneurons (Jankowska E., Spinal interneuronal systems: identification,multifunctional character and reconfigurations in mammals, J Physiol,533 (Pt 1):31-40 (May 15 2001)) which, combined with the weak excitatoryactivity of residual motor axons descending through the cervicothoracicinjury, achieved a level of excitation that was sufficient to fire themotoneurons and/or 2) axonal regeneration or sprouting may have beeninduced via activity-dependent mechanisms occurring over a period ofmonths. It is highly significant from a neurobiological as well as aclinical perspective that this voluntary control was manifested only inthe presence of continuous tonic epidural stimulation. This demonstratesthat by elevating the level of spinal interneuronal excitability to somecritical, but sub-threshold level, voluntary movements can be regained.Dimitrijevic M R, Gerasimenko Y, Pinter M M, Evidence for a spinalcentral pattern generator in humans, Ann NY Acad Sci, 16; 860:360-376(November 1998). These same mechanisms may also explain the improvedautonomic function in bladder, sexual, vasomotor, and thermoregulatoryactivity that has been of benefit to the subject. The areas oflumbosacral spinal cord stimulated included at least parts of the neuralcircuits that regulate these autonomic functions and may have alsoresulted in activity-dependent changes. In other words, given that thebroad areas of the lumbosacral spinal cord stimulated include at leastparts of the neural circuits that regulate these autonomic functions,these changes might have been expected if the neural networkscontrolling these autonomic functions are activity-dependent.

These data demonstrate that humans have conserved spinal locomotorcircuitry as found in other mammals that include: 1) transition from alow level activity state to one that can generate active standing in thepresence of tonic epidural stimulation; 2) gate tonic electricallyevoked responses according to the task specific sensory input, resultingin specific patterns of coordination within and between the motor pools;3) use appropriate task specific sensory input to control the level andtiming of neural excitation sufficient to generate independent standingand facilitate stepping; and 4) to mediate voluntarily initiatedmovement of the lower limbs in the presence of epidural stimulation. Ahigher level of improvement in motor function may be achieved with theaddition of pharmacological agents not only in spinal cord injury butalso with other neuromotor disorders. See Fuentes R, Petersson P,Siesser W B, Caron M G, Nicolelis M A, Spinal cord stimulation restoreslocomotion in animal models of Parkinson's disease, Science,323(5921):1578-1582 (Mar. 20, 2009).

In Example 1, epidural stimulation of the human spinal cord circuitrycombined with task specific proprioceptive input resulted in novelpostural and locomotor patterns. After seven months of stimulation andstand training, supraspinally mediated movements of the legs weremanifested only in the presence of epidural stimulation. Task specifictraining with epidural stimulation may have reactivated previouslysilent spared neural circuits or promoted plasticity. Thus, suchinterventions may provide a viable clinical approach for functionalrecovery after severe paralysis.

The above example supports the following. First, it is possible tostimulate the lumbosacral spinal cord with a modest, but sufficientlevel of intensity to enable the sensory input from the lower limbs toserve as a source of control of standing and to some degree of stepping.Second, the ability to stand for greater durations increases with dailystand training. Third, after months of stand training in the presence ofepidural stimulation, there was sufficient supraspinal and spinalreorganization to enable conscious control of movements of the lowerlimbs. Fourth, extensive reorganization of supraspinal and spinal motorsystems can occur in response to activity-dependent interventions in anindividual with complete paralysis for more than 3 years after a lowercervical-upper thoracic spinal cord injury. None of these observationsin a human subject with this severity of injury have been madepreviously.

Some additional publications discussing related technologies include thefollowing:

-   1. Gerasimenko Y, Roy R R, Edgerton V R., Epidural stimulation:    comparison of the spinal circuits that generate and control    locomotion in rats, cats and humans, Exp Neurol, 209(2):417-425    (February 2008);-   2. Grillner S, Wallen Peter, Central pattern generators for    locomotion, with special reference to vertebrates, Ann Rev Neurosci,    8:233-261 (1985);-   3. Grillner S., The motor infrastructure: from ion channels to    neuronal networks, Nat Rev Neurosci, 4(7):573-586 (July 2003);-   4. Grillner S, Zangger P., On the central generation of locomotion    in the low spinal cat, Exp Brain Res; 34:241-261 (1979);-   5. de Leon R D, Hodgson J A, Roy R R, Edgerton V R., Full    weight-bearing hindlimb standing following stand training in the    adult spinal cat, J Neurophysiol, 80:83-91 (1998);-   6. Harkema S, Schmidt-Read M, Lorenz D, Edgerton V R, Behrman A.,    Functional recovery in individuals with chronic incomplete spinal    cord injury with intensive activity-based rehabilitation, Arch Phys    Med Rehab, InPress;-   7. Minassian K, Persy I, Rattay F, et al., Human lumbar cord    circuitries can be activated by extrinsic tonic input to generate    locomotor-like activity, Hum Mov Sci, 26:275-95 (2007);-   8. Jilge B, Minassian K, Rattay F, et al., Initiating extension of    the lower limbs in subjects with complete spinal cord injury by    epidural lumbar cord stimulation, Exp Brain Res, 154(3):308-26    (2004); and-   9. Fuentes R, Petersson P, Siesser W B, Caron M G, Nicolelis M A.,    Spinal cord stimulation restores locomotion in animal models of    Parkinson's disease, Science, 323(5921):1578-1582 (Mar. 20, 2009).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentireties for all purposes.

The foregoing described embodiments depict different componentscontained within, or connected with, different other components. It isto be understood that such depicted architectures are merely exemplary,and that in fact many other architectures can be implemented whichachieve the same functionality. In a conceptual sense, any arrangementof components to achieve the same functionality is effectively“associated” such that the desired functionality is achieved. Hence, anytwo components herein combined to achieve a particular functionality canbe seen as “associated with” each other such that the desiredfunctionality is achieved, irrespective of architectures or intermedialcomponents. Likewise, any two components so associated can also beviewed as being “operably connected,” or “operably coupled,” to eachother to achieve the desired functionality.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art that,based upon the teachings herein, changes and modifications may be madewithout departing from this invention and its broader aspects and,therefore,

The invention claimed is:
 1. A method comprising: positioning a humanpatient in a training device, the patient having a neurologicallyderived paralysis in a portion of the patient's body, the trainingdevice being configured to assist with physical training that isconfigured to induce neurological signals in the portion of thepatient's body having the paralysis, the patient having a spinal cordwith at least one selected spinal circuit that has a first stimulationthreshold representing a minimum amount of stimulation required toactivate the at least one selected spinal circuit, and a secondstimulation threshold representing an amount of stimulation above whichthe at least one selected spinal circuit is fully activated and addingthe induced neurological signals has no additional effect on the atleast one selected spinal circuit, the induced neurological signalsbeing below the first stimulation threshold and insufficient to activatethe at least one selected spinal circuit; and applying electricalstimulation to a portion of a spinal cord of the patient, the electricalstimulation being below the second stimulation threshold such that theat least one selected spinal circuit is at least partially activatableby the addition of at least one of (a) a second portion of the inducedneurological signals, and (b) supraspinal signals.
 2. The method ofclaim 1, wherein the paralysis is a motor complete paralysis.
 3. Themethod of claim 1, wherein the paralysis is a motor incompleteparalysis.
 4. The method of claim 1, wherein the first portion of theinduced neurological signals is the same as the second portion of theinduced neurological signals.
 5. The method of claim 1, wherein theelectrical stimulation does not directly activate muscle cells in theportion of the patient's body having the paralysis.
 6. The method ofclaim 1, wherein the induced neurological signals comprise at least oneof postural proprioceptive signals, locomotor proprioceptive signals,and the supraspinal signals.
 7. The method of claim 1, wherein theparalysis was caused by a spinal cord injury classified as motorcomplete.
 8. The method of claim 1, wherein the paralysis was caused bya spinal cord injury classified as motor incomplete.
 9. The method ofclaim 1, wherein the paralysis was caused by an ischemic or traumaticbrain injury.
 10. The method of claim 1, wherein the paralysis wascaused by an ischemic brain injury that resulted from a stroke or acutetrauma.
 11. The method of claim 1, wherein the paralysis was caused by aneurodegenerative brain injury.
 12. The method of claim 11, wherein theneurodegenerative brain injury is associated with at least one ofParkinson's disease, Huntington's disease, Alzheimer's, ischemia,stroke, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis(PLS), and cerebral palsy.
 13. The method of claim 1, wherein theelectrical stimulation is applied by an electrode array that isimplanted epidurally in the spinal cord of the patient.
 14. The methodof claim 13, wherein the electrode array is positioned at at least oneof a lumbosacral region, a cervical region, and a thoracic region of thespinal cord.
 15. The method of claim 1, wherein the paralysis was causedby a spinal cord injury at a first location along the spinal cord, andthe electrical stimulation is applied by an electrode array that isimplanted epidurally on the spinal cord of the patient at a secondlocation below the first location along the spinal cord relative to thepatient's brain.
 16. The method of claim 1, wherein the physicaltraining comprises at least one of standing, stepping, reaching, movingone or both legs, moving one or both feet, grasping, and stabilizingsitting posture.
 17. The method of claim 1, wherein when activated, theat least one selected spinal circuit enables voluntary movement ofmuscles involved in at least one of standing, stepping, reaching,grasping, voluntarily changing positions of one or both legs, voidingthe patient's bladder, voiding the patient's bowel, postural activity,and locomotor activity.
 18. The method of claim 1, wherein whenactivated, the at least one selected spinal circuit enables or improvesautonomic control of at least one of cardiovascular function, bodytemperature, and metabolic processes.
 19. The method of claim 1, whereinwhen activated, the at least one selected spinal circuit facilitatesrecovery of at least one of an autonomic function, sexual function,vasomotor function, and cognitive function.
 20. The method of claim 1,further comprising: administering one or more neuropharmaceutical agentsto the patient.
 21. The method of claim 20, wherein the one or moreneuropharmaceutical agents comprise at least one of a serotonergic drug,a dopaminergic drug, a noradrenergic drug, a GABAergic drug, andglycinergic drugs.
 22. The method of claim 20, wherein the one or moreneuropharmaceutical agents comprise at least one of 8-OHDPAT, Way100.635, Quipazine, Ketanserin, SR 57227A, Ondanesetron, SB 269970,Methoxamine, Prazosin, Clonidine, Yohimbine, SKF-81297, SCH-23390,Quinpirole, and Eticlopride.
 23. The method of claim 1, wherein theelectrical stimulation is defined by a set of parameter values,activation of the at least one spinal circuit generates a quantifiableresult, and the method further comprises: repeating the method of claim1 using electrical stimulation having different sets of parametervalues; obtaining quantifiable results generated by each repetition ofthe method; executing a machine learning method on at least onecomputing device, the machine learning method building a model of arelationship between the electrical stimulation applied to the spinalcord and the quantifiable results generated by activation of the atleast one spinal circuit; and selecting a new set of parameters based onthe model.
 24. The method of claim 23, wherein the machine learningmethod implements a Gaussian Process Optimization.
 25. The method ofclaim 1, wherein the training device comprises a robot training deviceconfigured to move automatically at least a portion of the portion ofthe patient's body having the paralysis.
 26. The method of claim 1,wherein the training device comprises a treadmill and a weight-bearingdevice configured to support at least a portion of the patient's bodyweight when the patient is positioned to use the treadmill.
 27. Themethod of claim 1, wherein the training device comprises a deviceconfigured to bear at least a portion of the patient's body weight whenthe patient transitions between sitting and standing.
 28. The method ofclaim 1, wherein the electrical stimulation comprises at least one oftonic stimulation and intermittent stimulation.
 29. The method of claim1, wherein the electrical stimulation comprises simultaneous orsequential stimulation of different regions of the spinal cord.
 30. Amethod of enabling one or more functions selected from a groupconsisting of postural and/or locomotor activity, voluntary movement ofleg position when not bearing weight, voluntary voiding of the bladderand/or bowel, return of sexual function, autonomic control ofcardiovascular function, body temperature control, and normalizedmetabolic processes, in a human subject having a neurologically derivedparalysis, the method comprising: stimulating the spinal cord of thesubject using an electrode array; and while subjecting the subject tophysical training that exposes the subject to relevant posturalproprioceptive signals, locomotor proprioceptive signals, andsupraspinal signals; wherein at least one of the stimulation andphysical training modulates in real time the electrophysiologicalproperties of spinal circuits in the subject so the spinal circuits areactivated by at least one of supraspinal information and proprioceptiveinformation derived from the region of the subject where the selectedone or more functions are facilitated.
 31. The method of claim 30,wherein the region where the selected one or more functions arefacilitated comprises one or more regions of the spinal cord thatcontrol the lower limbs or the upper limbs.
 32. The method of claim 30,wherein the region where the selected one or more functions arefacilitated comprises one or more regions of the spinal cord thatcontrol at least one of the subject's bladder and the subject's bowel.33. The method of claim 30, wherein the physical training comprises atleast one of standing, stepping, sitting down, laying down, reaching,grasping, stabilizing sitting posture, and stabilizing standing posture.34. The method of claim 30, wherein the electrode array is an epidurallyimplanted electrode array.
 35. The method of claim 34, wherein theepidurally implanted electrode array is placed over at least one of alumbosacral portion of the spinal cord, a thoracic portion of the spinalcord, and a cervical portion of the spinal cord.
 36. The method of claim30, wherein the electrode array comprises one or more electrodesstimulated in a monopolar configuration.
 37. The method of claim 30,wherein the electrode array comprises one or more electrodes stimulatedin a bipolar configuration.
 38. The method of claim 30, wherein theelectrode array comprises a plurality of electrodes having aninterelectrode spacing between adjacent electrodes of about 500 μm toabout 1.5 mm.
 39. The method of claim 30, wherein the stimulationcomprises at least one of tonic stimulation, and intermittentstimulation.
 40. The method of claim 30, wherein the stimulationcomprises simultaneous or sequential stimulation of different spinalcord regions.
 41. The method of claim 30, wherein the stimulationpattern is under control of the subject.
 42. The method of claim 30,wherein the physical training comprises inducing a load bearingpositional change in the region of the subject where locomotor activityis to be facilitated.
 43. The method according to claim 42, wherein theload bearing positional change in the subject comprises at least one ofstanding, stepping, reaching, and grasping.
 44. The method of claim 30,wherein the physical training comprises robotically guided training. 45.The method of claim 30, further comprising: administering one or moreneuropharmaceuticals.
 46. The method of claim 30, wherein the one ormore neuropharmaceuticals comprises at least one of a serotonergic drug,a dopaminergic drug, a noradrenergic drug, a GABAergic drug, and aglycinergic drug.
 47. A method for use with a human patient having aspinal cord, and a neurologically derived paralysis in a portion of thepatient's body, the method comprising: implanting an electrode array onthe patient's spinal cord; positioning the patient in a training deviceconfigured to assist with physical training that is configured to induceneurological signals in the portion of the patient's body having theparalysis, the patient's spinal cord having at least one selected spinalcircuit that has a first stimulation threshold representing a minimumamount of stimulation required to activate the at least one selectedspinal circuit, and a second stimulation threshold representing anamount of stimulation above which the at least one selected spinalcircuit is fully activated and adding the induced neurological signalshas no additional effect on the at least one selected spinal circuit,the induced neurological signals being below the first stimulationthreshold and insufficient to activate the at least one selected spinalcircuit; and applying electrical stimulation to a portion of a spinalcord of the patient, the electrical stimulation being below the secondstimulation threshold such that the at least one selected spinal circuitis at least partially activatable by the addition of at least one of (a)a second portion of the induced neurological signals, and (b)supraspinal signals.
 48. The method of claim 47 for use with the spinalcord having a dura, wherein the electrode array is implanted on the duraof the patient's spinal cord.
 49. A system for use with a human patienthaving a spinal cord with a dura, and a neurologically derived paralysisin a portion of the patient's body, the system comprising: a trainingdevice configured to assist with physically training of the patient,when undertaken, the physical training inducing neurological signals inthe portion of the patient's body having the paralysis; an implantableelectrode array configured to be implanted on the dura of the patient'sspinal cord; and a stimulation generator connected to the implantableelectrode array, the stimulation generator being configured to applyelectrical stimulation to the implantable electrode array,electrophysiological properties of at least one spinal circuit in thepatient's spinal cord being modulated by the electrical stimulation andat least one of a first portion of the induced neurological signals andsupraspinal signals such that the at least one spinal circuit is atleast partially activatable by at least one of (a) the supraspinalsignals and (b) a second portion of the induced neurological signals.50. The system of claim 49, wherein the at least one selected spinalcircuit that has a first stimulation threshold representing a minimumamount of stimulation required to activate the at least one selectedspinal circuit, and a second stimulation threshold representing anamount of stimulation above which the at least one selected spinalcircuit is fully activated and adding the induced neurological signalshas no additional effect on the at least one selected spinal circuit,the induced neurological signals and supraspinal signals are below thefirst stimulation threshold and insufficient to activate the at leastone selected spinal circuit; and the electrical stimulation applied tothe implantable electrode array is below the second stimulationthreshold.
 51. A system for use with a patient having a neurologicallyderived paralysis in a portion of the patient's body, the systemcomprising: means for physically training the patient to induceneurological signals in the portion of the patient's body having theparalysis; and means for applying electrical stimulation to a portion ofa spinal cord of the patient, electrophysiological properties of atleast one spinal circuit in the patient's spinal cord being modulated bythe electrical stimulation and at least one of a first portion of theinduced neurological signals and supraspinal signals such that the atleast one spinal circuit is at least partially activatable by at leastone of (a) the supraspinal signals and (b) a second portion of theinduced neurological signals.